tbuckley/cabot-search huggingface dataset:
Association of FLT3 and NPM1 mutations in patients with acute myeloid leukemia with metabolomic patterns determined by mass spectrometry.
Authors: Selami Kocak Toprak, Selin Gerekci Yesilyurt, Derya Koyun, Muhit Ozcan, Can Özen
Journal: Journal of Clinical Oncology (2023)

e19003 Background: Patients diagnosed with Acute Myeloid Leukemia (AML) are categorized into risk groups based on cytogenetic and molecular abnormality tests, which determine the specific treatment regimes. Since mutation tests take time and some emergency patients require immediate treatment, a method to provide fast clinical data that will be the basis for initial treatment regime is needed. Aim of the study is to discover patterns associated with FLT3 and NPM1 mutations in AML patients, which will provide a fast clinical information to clinicians. The hypothesis is based on the previous studies which indicate a link between NPM1 and FLT3 mutations with metabolism. The mutations were chosen based on their high frequency in AML patients and their critical role in risk group determination. Methods: All AML patients (n = 42) and healthy individual samples (n = 16) were obtained from Ankara University Hematology Department. Patient groups were divided into five groups based on the mutation status. Pattern determination of the mutations was achieved by LC-MS/MS measurements of amino acid and acyl carnitine panels that are highly associated with metabolism. After preprocessing of the raw data, univariate (ANOVA) and multivariate analyses (PCA and PLS-DA) were performed to define class discrimination between sample groups. The remarkable analytes that have significant power in the discrimination were determined by VIP analysis. The developed model was validated with K-Fold cross validation method and permutation test. The most significant pathways in class discrimination were identified with pathway analysis. Visualization was accomplished via Metaboanalyst 5.0 software. Results: Principal Component Analysis (PCA) showed that 79% of the total variance of the sample groups was explained by the model. In order to increase class discrimination, Partial Least Squares-Discriminant Analysis (PLS-DA) was performed. R2Y and Q2 were found as 0.845 and 0.619, respectively. PLS-DA model was validated with K-fold analysis and permutation test. In all the validation experiments, a low cross-validation error was observed. In VIP analysis, the most significant analytes that cause the class discrimination were found as C0 carnitine, glutamic acid, aspartic acid, respectively. In the pathway enrichment analysis performed with these analytes, aminoacyl t-RNA biosynthesis, arginine biosynthesis, valine-leucine-isoleucine biosynthesis were found as statistically significant pathways responsible for the class discrimination. Conclusions: A preliminary model based on the targeted metabolomics approach was developed for the prediction of mutation status of NPM1 and FLT3 proteins in AML patients. Proposed model has a high fit value, validity, and strong predictive power. The reliability and validity of the model can be further increased by future multicenter studies.
Racial bias in multiple myeloma clinical trials: Racial minorities continue to miss out on treatment advances.
Authors: Ranjit Jasaraj, Suman Gaire, Ekaterina Proskuriakova, Ranjana Jasaraj, Amany R. Keruakous
Journal: Journal of Clinical Oncology (2023)

e20009 Background: Adequate representation of participants based on race and ethnicity in a clinical trial helps ensure the results' generalizability. There is a disparity in the participation of minorities in oncology clinical trials despite higher incidence and disease burden in them. The incidence of Multiple Myeloma (MM) in AA (African American) is twice as compared to White, and they are twice as likely to die from MM compared to White. Methods: We queried ClinicalTrials.gov in February 2023 for all completed interventional trials with the published results for Multiple Myeloma in the US. Demographic data were collected from all the studies. If not available, the primary manuscript was searched using the trial number. We excluded the studies involving other malignancies and conducted outside of the USA. Trials on prevention, diagnostics, supportive care, and antibiotics were also excluded. Incidence data of Multiple myeloma was obtained from the SEER database for each ethnicity and race. Results: Out of 194 trials included in our study, 133 (68.56%) reported at least either race or ethnicity. Of these trials, 83 (42.78) reported race, 124 (63.91) reported ethnicity, and 77 (39.69) reported both race and ethnicity. 5.67% of the trial participants were reported as Hispanic race. White, AA, and Asian represented 79.82%, 11.36%, and 3.10% of the trial participants, respectively. The number of trials reporting race or ethnicity has increased when comparing the trials conducted between 2001-2011 and 2012-2022 (58.3% vs. 90.3%); OR 6.4; 95% CI 2.77-17.98; p&lt;0.001. Participation of Asians increased (2% vs. 5.5%; p&lt;0.0005), while there were slight changes among AA (11.7% vs. 10.6%, p=0.1475), Hispanic (5.4% vs. 6%; p=0.3863), and White (80.8% vs. 77.8%, p=0.208) between 2001-2011 and 2012-2022. Conclusions: Despite ongoing efforts to improve the diversity of minorities in oncology trials, they are still under-enrolled in multiple myeloma. More studies and interventions are needed to address this disparity. [Table: see text]
Multi-omics study of the genomic features and clinical characteristics of hepatic sarcomatoid carcinoma located at different sites.
Authors: Yanchun Li, Wei Guo, Mengjun Mo, Yangcan Li, Qingqing He, Baofeng Lian, Xiaoliang Shi, Guomin Lin, Fei Pang
Journal: Journal of Clinical Oncology (2023)

e15153 Background: Hepatic sarcomatoid carcinoma (HSC) is a rare and highly malignant tumor, which accounts for less than 2% of hepatic carcinoma. HSC can occur in the liver (Sarcomatoid hepatocellular carcinoma, SHCC) or in the intrahepatic bile duct (Sarcomatoid intrahepatic cholangiocarcinoma, SiCCA). We aimed to compare the clinical characteristics and genomic features between SHCC and SiCCA. Methods: In this study, we recruited 20 patients who were pathologically diagnosed with HSC from January 2018 to February 2021 in Hunan Provincial People’s Hospital. Whole exome sequencing and PD-L1 expression detected by immunohistochemistry were performed on the qualified tissue samples obtained from18 (14 with SHCC and 4 with SiCCA) of the enrolled patients. Tests were performed in OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Fisher test was used to determine the association between two categorical variables, and P&lt; 0.05 was considered statistically significant. Results: A total of 15 cases of SHCC and 5 cases of SiCCA were enrolled in this study, with median age of 59 years old (ranged from 34 to 75 years old). Among them, 15 (75%) were diagnosed as AJCC stage III-IV. Compared with SiCCA, we observed a significant higher proportion of undifferentiated samples in SHCC ( P&lt; 0.001) (Table 1). The most commonly mutated genes of HSC included TP53 (64% in SHCC and 75% in SiCCA) and TTN (43% in SHCC and 100% in SiCCA). The most commonly mutated genes in SHCC also included TERT (43%), CCDC168 (36%), and LATS1 (36%), and that in SiCCA also included CDKN2A (50%), KRAS (50%), and CDKN2B (50%). All these genes were mainly enriched in cell cycle and ERBB pathway. In addition, amplifications of HYDIN, C4A, LRRC37A and deletions of CDKN2A, NTRK2, NTRK3, NRG1, PAX3, OR4K5, TPP2 and KRTAP4-6 were detected in the SHCC cohort, and amplifications of ZDHHC11, PMS2 and deletions of NRG1 and CDKN2A were detected in the SiCCA cohort. We also assessed TMB and PD-L1 status among these two cohorts. We found that 86% (12/14) of SHCC and 100% (4/4) of SiCCA had TMB of lower than 10 mutations/Mb. The expression of PD-L1 was positive (CPS &gt; = 1) in 86% (12/14) of SHCC and 75% (3/4) of SiCCA. Conclusions: We are the first to discover the significant differences in tumor differentiation between SHCC and SiCCA. We also profiled the mutational characteristics, TMB status, and PD-L1 status of HSC, shedding light on the precision medicine of HSC. [Table: see text]
Efficacy of PD-1 inhibitors for colorectal cancer and polyps in patients with Lynch syndrome.
Authors: Jiehai Yu, Binyi Xiao, Jinghua Tang, Dandan Li, Fang Wang, Ya Ding, Kai Han, Ling-Heng Kong, Yi-hong Ling, Wei-Jian Mei, Zhigang Hong, Leen Liao, Wanjun Yang, Zhi-Zhong Pan, Xiao-Shi Zhang, Wu Jiang, Pei-Rong Ding
Journal: Journal of Clinical Oncology (2023)

e15521 Background: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. Methods: LS patients with CRC who had evaluable tumors and received ≥2 cycles of PD-1 inhibitors were included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies including anti cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analyzed. Results: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3 to 71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses (CRs) and 42.7% (n = 32) partial responses (PRs). Three cases of LS CRCs displaying pMMR/MSS or discordant MMR/MSI status were not responsive even with a high tumor mutation burden (TMB). Mucinous/signet-ring cell differentiation was associated with a lower ORR ( P= 0.013). The 3-year OS and PFS was 91.2% and 81.0%, respectively. Colorectal polyp/adenoma was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment and their maximum diameters were all larger than 7mm. Conclusions: PD-1 inhibitors are highly effective for dMMR/MSI-H LS CRCs, but not for pMMR/MSS LS CRCs or those displaying discordant MMR/MSI status or mucinous/signet-ring cell CRC. Some of the large LS adenomas may also be sensitive to anti-PD-1 treatment.
Disparities in presentation, treatment, and overall survival for South Asian American patients with colorectal cancer.
Authors: Kaleem Sohail Ahmed, Clayton Thomas Marcinak, John K. Krebsbach, Andrea M Schiefelbein, Patrick Varley, Noelle K. LoConte, Syed Nabeel Zafar
Journal: Journal of Clinical Oncology (2023)

e15554 Background: The South Asian population in America is growing. Colorectal Cancer (CRC) is one of the most common cancers amongst South Asian Americans (SAA), however few studies have looked at differential presentation, treatment, and outcomes. The objective of this study was to compare differences in presentations, and investigate disparities in treatment and overall survival (OS) amongst SAAs compared with non-Hispanic whites (NHW). Methods: We performed a retrospective analysis of patients with colon or rectal adenocarcinoma in the National Cancer Database (NCDB) years 2004-2020. We compared differences in patient demographics, socioeconomics, stage at presentation, and treatments received between SAA and NHW populations using chi square, and t tests as applicable. OS was evaluated using Kaplan-Meier analysis and the log-rank test. Multivariable Cox regression stratified by stage was used to compare OS between the two groups. Results: We analyzed data from 773,223 NHW and 3,448 SAA patients with colon cancer (CC) and 285,769 NHW and 1,826 SAA patients with RC. At presentation SAAs were younger (61.2 years vs 69.2 years, p&lt;0.001 for CC, and 57.9 vs 63.9, p&lt;0.001 for RC), less likely to have government insurance (44.1% vs 64.1%, p&lt;0.001 for CC, and 35.4% vs 50.6%, p&lt;0.001 for RC), more likely to be living in metropolitan areas (97.9% vs 83.2%, p&lt;0.001 for CC, and 97.4% vs 81.0%, p&lt;0.001 for RC), and more likely to have advanced stages of disease (47.4% vs 42.7%, p&lt;0.001 for CC, and 40.9% vs 38.9%, p&lt;0.001 for RC). SAAs had significantly longer delay in receipt of surgical intervention or radiation therapy (p &lt;0.001) and were less likely to receive surgery for stage 4 for CC (54.6% vs 60.5%, p&lt;0.001). On multivariate cox regression, adjusted for age, sex, insurance status, urban/rural location, and comorbid conditions, SAAs with either colon or rectal cancer were more likely to survive across all cancer stages (p&lt;0.001). Conclusions: In this national study, when compared to NHW patients, SAA patients with CRC, present at younger ages and with more aggressive disease. Despite SAAs being less likely to receive timely cancer care, they have better overall survival. [Table: see text]
Pan-cancer detection and tissue-of-origin identification by whole-genome sequencing of plasma cell-free DNA.
Authors: Wei Guo, Wei Wang, Yanqing Zhou, Heng An, Yanhua Lv, Zuoquan Yang, Chao Lu, Xiaoni Zhang, Mingyan Xu, Shifu Chen
Journal: Journal of Clinical Oncology (2023)

3055 Background: Despite notable advances in cancer therapeutics, much of the mortality of human cancers results from late diagnosis. The early detection of cancer remains an unmet need that can benefit the effective treatments and better prognosis. Cell-free DNA (cfDNA) in the circulation provides an emerging diagnostic method for non-invasive cancer screening. The fragmentation signatures of cfDNA originating from different cell types or malignancies display distinct patterns, suggesting the potential as cancer biomarkers. This study aims to investigate the fragmentation profiles of cfDNA in several cancer types, and to develop a new approach for pan-cancer detection and tissue-of-origin identification. Methods: Plasma samples from 739 patients with lung (N=577), colorectal (N=98), breast (N=51) and liver (N=13) cancers, as well as 716 healthy individuals were collected in this study. Cell-free DNA was isolated and used to generate the whole-genome sequencing data. We developed an approach called PatternWGS (Pan-cancer detection and tissue-of-origin identification by whole-genome sequencing) to analyze the DNA fragmentation patterns comprehensively. Fragmentation features integrating cfDNA fragment size distribution, frequency of end motif sequence, and copy number variation were utilized to construct the optimal prediction model. We presented a multi-cancer detection model for distinguishing individuals with and without cancer using Generalized Linear Models (glmnet), and further built a cancer-origin model to predict cancer types using Random Forest algorithm. Training and testing occurred on randomly selected sampling splits of 60% and 40% of the data, respectively. Features selection and model construction were performed by only training cohort, and the test set was solely used for performance evaluation. Results: A larger proportion of shorter cfDNA fragments in cancers was observed. We proposed a fragment score indicating the degree of short fragmentation, and this fragment score was significantly higher in cancers (p&lt;0.001). Several end motifs were identified to be specifically enriched in cancer patients. The multi-cancer detection model reached an area under the curve (AUC) of 0.98, with the sensitivity of 93% at 95% specificity. The sensitivity of detecting lung, colorectal, breast, and liver cancers reached 94.2%, 87%, 100% and 100% respectively, at 95% specificity. The cancer-origin model demonstrated an overall accuracy of 81.7% for the identification of tissue of origin. Conclusions: Our prediction model demonstrated a superior performance for multi-cancer detection and cancer origin prediction, suggesting the potential of plasma cfDNA fragmentation signatures as non-invasive biomarkers for early cancer detection in clinical. The distinct fragmentation patterns in cancer provide new insight to understand the mechanism of tumorigenesis.
When is neoadjuvant chemotherapy indicated in rectal neuroendocrine tumors? An analysis of the National Cancer Database.
Authors: Rachel Gefen, Sameh Hany Emile, Nir Horesh, Zoe Garoufalia, Michael Freund, Steven D Wexner
Journal: Journal of Clinical Oncology (2023)

e15631 Background: Rectal neuroendocrine tumors (rNET) are rare and challenging to manage. While most patients with small rNET can be definitively treated with local excision, the role of chemotherapy in general and neoadjuvant therapy specifically in managing advanced rNET has not been well established. Therefore, this study aimed to determine which patients with rNET may gain a survival benefit from neoadjuvant chemotherapy. Methods: A retrospective cohort analysis of all patients who underwent surgical resection of rNET in the US National Cancer Database (NCDB) (2004-2019) was performed. First, univariate and multivariate cox regression analyses were performed to determine the independent predictors of poor overall survival (OS) and define the high-risk groups. Afterwards, stratified OS analyses were performed for each high-risk group to assess whether neoadjuvant chemotherapy had a survival benefit in each group. Results: 1837 patients (49.8% female; mean age 56.6 ±12.3 years) underwent radical resection of a rectal neuroendocrine tumor. Tumors &gt; 20 mm in size, clinical T4 tumors, poorly differentiated tumors, and metastatic disease were independent predictors of worse OS and were defined as high risk groups. Neoadjuvant chemotherapy did not have a significant survival benefit in any of the high-risk groups, except for patients with high-grade rNETs where neoadjuvant therapy significantly improved OS to a mean of 30.9 months compared to 15.9 months when neoadjuvant therapy was not given (p = 0.006). Conclusions: Neoadjuvant chemotherapy improved OS of patients with high-grade rNET by 15 months and may be indicated for this group.
Trends of colorectal cancer and associated factors in the United States: A SEER registry analysis.
Authors: Ifrah Fatima, Ben Ponvilawan, Dheera Grover, Adriana Matutino Kahn, Anuj Shrestha, Murali Dharan
Journal: Journal of Clinical Oncology (2023)

e15553 Background: Colorectal cancer (CRC) is the fourth most common type of cancer diagnosed in the US, accounting for 8% of new cancers diagnosis in 2022. Despite advancements in the screening and diagnostic methods, CRC still contributes significantly to cancer-related healthcare burden ($24.3 billion/year). Several factors including wider demographic reach, socioeconomic equity, age at screening, CRC awareness, and social media platforms have contributed to this changing landscape. We conducted a Surveillance, Epidemiology, and End Results Program (SEER) based analysis to determine the trends of CRC diagnosis and potential risk factors. Methods: Individual data was acquired from SEER 9 registry from 1975-2018. R was used for the statistical analyses. Univariate logistic regression was performed to evaluate the relation between year of diagnosis and each variable (year of diagnosis, household income, household location, sex, and race) at the time of diagnosis. Multivariate regression was performed for individuals in all age group and less than 45 years of age. P-value less than 0.05 was considered significant. Results: In total 550,221 CRC patients were retrieved. 91.7% (504,709) were ≥50 years and 4.5% (24,674) were &lt; 45. Over the years, there was a notable increase in percentage of patients with age &lt; 45 years amongst all CRC patients (3.3% in 1975-1979 vs. 7.4% in 2015-2018) with females increasing faster than males. A remarkable drop in percentage of CRC case in individuals ≥50 years amongst all gastrointestinal cancers (63.0% in 1975-1979 vs. 44.8% in 2015-2018) with females decreasing faster than males. There were no interactions between the year of diagnosis and above variables. Multivariate logistic regression exhibited lower odds of CRC diagnosis in all non-white races and males, but higher odds in lower household income and non-metropolitan areas (Table 1). Subgroup analysis of age group &lt; 45 years pertained similar odds. Conclusions: The striking drop in number of CRC cases above 50 years of age can be attributed to earlier detection with screening methods, and other socioeconomic factors like healthcare literacy and awareness. Increased representation of younger population over the years reaffirms the recent change in guidelines for screening. Further studies focusing on determining the impact in outcomes of screening methods in younger population and equality of implementation in disadvantaged population are highly warranted. [Table: see text]
Performance of the OncoUrine test on the predictive capacity of non-muscle-invasive bladder cancer patients who are candidates for repeated transurethral resection.
Authors: Xiao Yang, Lingkai Cai, Yiming Liang, Yaqun Xin, Tonghui Ma, Qiang Lyu
Journal: Journal of Clinical Oncology (2023)

e16595 Background: According to European Association of Urology (EAU) guidelines, repeated transurethral resection of bladder tumor (re-TURBT) is recommended in a large percentage of high-risk non–muscle-invasive bladder cancers (NMIBC) due to possibility of incomplete initial TURBT. But so far, no diagnostic tests able to improve patients’ stratification exist to reduce negative biopsy ratio of re-TURBT. To evaluate the value of the OncoUrine test for the predictive capacity of biopsy findings on re-TURBT, a prospective multi-center clinical trial was designed. Methods: This was a blinded, observational, prospective multicenter study (NCT05112523). Between December 2020 and September 2022, patients with a confirmed diagnosis of high-risk NMIBC at three study centers were enrolled. The inclusion criteria were ≥age 22 years old, prepare for re-TURBT following EAU guidelines, able to produce 100 ml of morning urine, and able to consent. Urine samples were collected from the enrolled patients for the OncoUrine tests before re-TURBT, and the test results were compared with the pathological results to calculate the performance. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel named OncoUrine. Results: Out of 109 patients enrolled, 93 were eligible for the performance analysis. In 33 cases, residual tumors were confirmed while the remaining 60 patients was found to have a result of negative pathological section. In the overall OncoUrine test results, variants from 11 genes showed positive mutations. TERT C228T, TP53, TERT C250T, ERBB2 and PIK3CA were on the top 5 of the list with other mutations from FGFR3, KRAS, HRAS, ERBB3, ERCC2, U2AF1, and ROHA. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the OncoUrine test for predicting pathological diagnosis were 81.8% (27/33), 81.7% (49/60), 89.1% (49/55), and 71.1% (27/38), respectively. Conclusions: Even for high-risk patients for whom re-TURBT is currently recommended, the OncoUrine test can accurately differentiate between cases with incomplete primary surgeries and those with no residual tumors. An interventional clinical trial is needed to further confirm the clinical value of this urine-based biopsy method on improving the selections of NMIBC patients. Clinical trial information: NCT05112523 .